Aromatic acetylcholinesterase inhibitors

ABSTRACT

Compounds of general formula (I), stereosiomers and pharmaceutically acceptable salts thereof, wherein each of Z and Z&#39; are independently H or F; Q is (a), CH(OH), (b); X is H, Br, Cl, F or CF 3  ; Y is H, Br, Cl, F, OH, OR 5 , OC(O)R 4 , N 3 , CN, NO 2 , SO 3  H, CO 2  R 4 , NH 2 , NHR 9 , NR 9  R&#39; 9 , C(R 6 )(R 7 )(V&#39;R 8 ) or C(O)R 7 , provided that when both Z and Z&#39; are F, then Y is H or F; V and V&#39; are each independently CH 2  or O; R 1  is H or CH 3  ; R 2 , R 9  and R&#39; 9  are each independently (C 1-6 )alkyl, or R 2  and V--R 3  taken together with the carbon atom to which they are attached form a 3-6 membered ring; R 3 , R 6 , R 7  and R 8  are each independently H, (C 1-6 )alkyl, or (C 3-6 )cycloalkyl; R 4  is H, (C 1-10 )alkyl, (C 0-4 )alkylene aryl or (C 3-8 )cycloalkyl; and R 5  is (C 1-10 )alkyl, benzyl, phenethyl or (C 3-6 )cycloalkyl, possess anticholinesterase activity and may be used in the treatment of Degenrativa Dementias.

This invention relates to the use of fluorinated aromatic compounds intreating diseases associated with deficiencies of cholinergictransmission in the central nervous system and methods for theirpreparation.

Compounds of the present invention have the following ##STR2##stereoisomers and pharmaceutically acceptable salts thereof, whereineach of Z and Z' are independently H or F;

Q is ##STR3## CH(OH), ##STR4## X is H, Br, Cl, F or CF₃ ; Y is H, Br,Cl, F, OH, OR₅, OC(O)R₄, N₃, CN, NO₂, SO₃ H, CO₂ R₄, NH₂, NHR₉, NR₉ R'₉,C(R₆)(R₇)(V'R₈) or C(O)R₇, provided that when both Z and Z' are F, thenY is H or F;

V and V' are each independently CH₂ or O;

R₁ is H or CH₃ ;

R₂, R₉ and R'₉ are each independently (C₁₋₆)alkyl, or R₂ and V--R₃ takentogether with the carbon atom to which they are attached form a 3-6membered ring;

R₃, R₆, R₇ and R₈ are each independently H, (C₁₋₆)alkyl, or(C₃₋₆)cycloalkyl;

R₄ is H, (C₁₋₁₀)alkyl, (C₀₋₄)alkylene aryl or (C₃₋₈)cycloalkyl; and

R₅ is (C₁₋₁₀)alkyl, benzyl, phenethyl or (C₃₋₆)cycloalkyl.

The present invention uses compounds of Formula I to treat patientshaving conditions responsive to the acetylcholinesterase-inhibitingproperties of the present compounds such as in the treatment ofDegenerative Dementias.

The terms "(C₁₋₆)alkyl" and "(C₁₋₁₀)alkyl" mean straight or branchedchain alkyl radicals containing respectively from 1 to 6 carbon atomsand from 1 to 10 carbon atoms, including, but not limited to, methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,t-butyl,n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl and so on. Likewise, the term"(C₀₋₄)alkylene aryl" can mean straight or branched chain alkylenegroups up to 4 carbon atoms such as ethylethylene, 2-methyltrimethylene,and so on. C₀ of course means no alkylene moiety attached to the aryl.

"Hydroxy(C₁₋₆)alkyl" means a (C₁₋₆)alkyl group having from 1 to 3hydroxy substituents thereon. Preferably, there is only one hydroxysubstituent at the alpha position (attached to the carbon atom which isdirectly attached to the phenyl).

"Ts" or "tosyl" means ##STR5## Tosyl derivatives mean ##STR6## wherein Ris C₁₋₆ alkyl.

"Aryl" includes both carbocyclic and heterocyclic moieties of whichphenyl, pyridyl, indolyl, indazolyl, furyl and thienyl are of primaryinterest; these moieties being inclusive of their position isomers suchas, for example, 2-, 3-, or 4-pyridyl, 2- or 3-furyl and thienyl, 1-,2-, or 3-indolyl or the 1- and 3-indazolyl, as well as the dihydro andtetrahydro analogs of the furyl and thienyl moieties. Also includedwithin the term "aryl" are such fused carbocyclic moieties aspentalenyl, indenyl, naphthalenyl, azulenyl, heptalenyl,acenaphthylenyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl,acephenanthrylenyl, aceanthrylenyl, triphenylenyl, pyrenyl, chrysenyland naphthacenyl. Also included within the term "aryl" are such otherheterocyclic radicals as 2- or 3-benzo[b]thienyl, 2- or3-naphtho[2,3-b]thienyl, 2- or 3-thianthrenyl, 2H-pyran-3-(or 4- or5-)yl, 1-isobenzofuranyl, 2H-chromenyl-3-yl, 2- or 3-phenoxathiinyl, 2-or 3-pyrrolyl, 4- or 3-pyrazolyl, 2-pyrazinyl, 2-pyrimidinyl,3-pyridazinyl, 2-indolizinyl, 1-isoindolyl, 4H-quinolizin-2-yl,3-isoquinolyl, 2-quinolyl, 1-phthalazinyl, 1,8-naphthyridinyl,2-quinoxalinyl, 2-quinazolinyl, 3-cinnolinyl, 2-pteridinyl,4aH-carbazol-2-yl, 2-carbazolyl, β-carbolin-3-yl, 3-phenanthridinyl,2-acridinyl, 2-perimidinyl, 1-phenazinyl, 3-isothiazolyl,2-phenothiazinyl, 3-isoxazolyl, 2-phenoxazinyl, 3-iso-chromanyl,7-chromanyl, 2-pyrrolin-3-yl, 2-imidazolidinyl, 2-imidazolin-4-yl,2-pyrazolidinyl, 3-pyrazolin-3-yl, 2-piperidyl, 2-piperazinyl,1-indolinyl, 1-isoindolinyl, 3-morpholinyl, benzo[[h]isoquinolinyl, andbenzo[b]furanyl, including the position isomers thereof except that theheterocyclic moieties cannot be attached directly through their nitrogenatoms. Aryl groups can be substituted or unsubstituted with one, two orthree substituents independently selected from C₁₋₆ alkyl, haloalkyl,alkoxy, thioalkoxy, aminoalkylamino, dialkylamino, hydroxy, halo,mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide.

When R₂ and V--R₃ are taken together, they may form a 3 membered ringwhich includes the carbon atom to which R₂ and V are attached (when R₃is H). Other rings formed may have 4, 5 and 6 members to the ring. Theterm 3-6 membered ring refers to the number of carbon atoms, and oxygenatoms (when V is O) comprising the structure of the ring.

" Stereoisomers" for the compounds of Formula I is a general term forall isomers of individual molecules that differ only in the orientationof their atoms in space. It includes mirror image isomers (enantiomers),geometric isomers (cis/trans), and isomers of compounds with more thanone chiral center that are not mirror images of one another(diastereoisomers), whichever forms are applicable to the compound.

The pharmaceutically acceptable salts of the compounds of Formula Iinclude salts formed with non-toxic organic or inorganic acids such as,for example, from the following acids: hydrochloric, hydrobromic,sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic,ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic,tartaric, citric, lactic, malic, mandelic, cinnamic, palmitic, itaconicand benzenesulfonic.

The term "patient" refers to a warm-blooded animal, such as for examplerats, mice, dogs, cats, guinea pigs, primates and humans. "Treating" apatient means to prevent or alleviate the patient's disease orcondition.

The term "Degenerative Dementia" as used herein means senile dementia,presenile dementia, degenerative dementia of the Alzheimer's type (whichincludes Alzheimer's Disease) and other types of progressivelydeteriorating organic mental syndromes in which there is impairment inshort-term and long-term memory. The Degenerative Dementia can be mild(impairment of work or social activities but able to live alone),moderate (some degree of supervision needed), or severe (continualsupervision required).

Impairment in short-term memory is the inability to learn newinformation and may be demonstrated by, for example, the patient'sinability to remember three objects after five minutes. Long-term memoryimpairment is the inability to remember information that was known inthe past and may be indicated by, for example, the patients' inabilityto remember past personal information such as their birthplace, address,occupation, what happened yesterday, etc., or the inability to rememberfacts of common knowledge. There is typically impairment in abstractthinking, impairment in judgment, personality changes or otherdisturbances of higher cortical functions.

The preparation of the compounds of Formula I may be accomplished in avariety of methods depending upon the specific combinations of variablesubstituents. The following general schemes illustrate only one waythese compounds may be made. Other analogous chemical reactions andprocedures may be utilized which may be known to those skilled in theart.

All moieties are as previously defined unless otherwise indicated.

SCHEME A:

To make sub-generic Formula II: ##STR7##

To make intermediates (A3), (A5) and (A7), the bromophenyl derivative(A1) is reacted with the appropriate aldehyde or ketone to produce thebenzyl alcohol derivative (A2) or phenethyl derivative (A4) is reactedwith the appropriate alkyl halide to produce the ether derivatives (A5).

Alternatively, intermediates (A3) or (A7) can be made by starting withaniline derivative (A8) and by acetylation producing (A9) which issubsequently brominated to produce (A10). The bromo derivative (A10) isdeacetylated to produce (A11) and subsequently deaminated to produce(A3) (A7).

Referring to Scheme B, to make compounds of the present inventionwherein Y is NH₂, the acid derivative (B1) is converted to the acylazide intermediate and then to the amine (B2) by the Curtiusrearrangement. The amine is protected (B3) then reacted with theappropriate ester to produce (B4) and subsequently deprotected (B5). Themethyloxy derivatives of (B5) can be reduced to the alcohol (B6) andsubsequently reduced to the alcohol (B7).

The protected amine ketone derivative (B4) is reduced to the alcohol(B8) which is subsequently deprotected (B9) or esterified anddeprotected (B10). The methoxy derivatives of (B10) can be reduced tothe alcohol (B11).

Preparation of the intermediates is shown from the bromo derivative(B13) which is alkylated with the appropriate alkylating agent andsubsequently carboxylated to produce the acid derivative (B1).Alternatively, the fluoro derivative (B15) can be alkylated to producederivative (B16) which can be carboxylated (B1). ##STR8##

To make compounds of the present invention wherein Y is the secondaryamine NHR₉ (Scheme C), the amine derivative (C1) is first protected withan appropriate protecting group at one position to avoid initialbis-alkylation of the amine. The unprotected site on the amine is thenalkylated by reaction with the appropriate alkyl-halide reagent,followed by hydrolysis, the secondary amine (C3) is produced. Anappropriate protecting group protects the secondary amine (C4) and stepspreviously described are performed to add the QCF₂ X moiety (C5). Again,when VT is methoxy, the compound can be transformed to the alcoholderivative (C6).

The secondary amine (C3) can be alkylated to produce the tertiary amine(C7). The QCF₂ X moiety as previously described, replaces the W moiety(C8) and the methoxy moiety (VT) can be transformed into the alcohol(C9). ##STR9## wherein Z and Z' are each H or F;

Y^(D) is Br, Cl, F, CN, N₃, NO₂, OH or SO₃ H. For the scheme,

T is R₃ except H for when V is O.

The amino derivative (D1) of Scheme D can be treated in a variety ofways to produce the moieties of Y^(D) as described hereafter. The esterderivative (D2) is hydrolyzed to produce the alcohol derivative (D3)which can subsequently be oxidized to the ketone (D4). If the ketonederivative (D4) has a VT moiety of methoxy, the alcohol derivative (D5)can be formed. Also, the ester moiety (D2) having a VT moiety of methoxycan form the alcohol derivative (D6) which can then be hydrolized toproduce the alcohol derivative (D7). ##STR10##

Phenol derivatives (E1) or (E5) are reacted with an appropriatealkylating agent or acyl halide agent to produce ether or esterderivatives (E2) and (E6). The ketone derivatives (E2) and (E6) arereduced to the alcohol derivatives (E3) and (E8). Prior to reduction,unprotected alcohols (E6) can be protected with, for example, t-butyl(E7) and subsequently deprotected (E10) if desired. The alcoholderivatives (E3) and (E8) can be acylated (E4) and (E9). ##STR11##

Referring to Scheme F, nitrile derivative (F1) is hydrolized oralcoholized to produce acid or ester derivatives or converted toaldehyde or ketone (F2) and subsequently oxidized to produce ketonederivative (F3). The alcohol derivative (F2) can be acylated to produceester derivatives (F5).

The alkylated derivatives G1 are made from steps previously described asshown in Scheme G. ##STR12## Step Aa:

Bromophenyl derivatives A1 are converted to their lithium salt with analkyl lithium reagent in diethyl ether or tetrahydrofuran at about -78°C. to about -60° C. for about 5-10 minutes, and then reacted at about-78° C. to about -60° C. for about one hour with an aldehyde or a ketoneR₁ COR₂ to produce benzyl alcohol derivatives A4, or reacted with aketone R₂ COCH₂ R₃ to produce benzyl alcohol derivatives A2.

Step Ab:

Benzyl alcohol derivatives A2 are heated to about +120° C. to about+130° C. for 3-6 hours with trimethylaluminum in benzene or toluene inthe presence of catalytic amount of water or acetic acid to producealkyl derivatives A3.

Step Ac:

Benzyl alcohol derivatives A4 are converted to their sodium salt withsodium hydride in tetrahydrofuran at room temperature and thoseintermediates are reacted with and alkyl halide R₃ X (R₃ ≠H and X beingpreferably Br or I) at room temperature for about 18 hours to produceether derivatives A5.

Step Ad:

Benzyl alcohol derivatives A2 are reacted with paratoluenesulfonylchloride in pyridine at 0° C. to 10° C. for 18 hours to produce tosylatederivatives A6.

Step Ae:

Tosylate derivatives A6 are reduced with lithium aluminum hydride intetrahydrofuran at reflux or in di-n-butyl ether at about 90° C. toabout 120° C. for about 3-6 hours to produce alkyl derivatives A7.

Step Af:

Aniline derivatives A8 are heated under reflux in acetic acid for about6-8 hours in the presence of catalytic amount of zinc powder to produceN-acetyl derivatives A9.

Step Ag:

N-acetyl derivatives A9 are treated with bromine in acetic acid at about30° C. to 40° C. for about 3-6 hours in the presence of catalytic amountof ferric chloride to produce N-acetylbromo derivatives A10.

Step Ah:

N-acetylbromo derivatives A10 are heated in a mixture of concentratedhydrochloric acid and ethanol for about one hour to producehydrochloride salt of bromoamino derivatives A11.

Step Ai:

Hydrochloride salts of bromoamino derivatives A11 are treated withsodium nitrite in acidic medium at about 0° C. to 5° C. and then withhypophosphorus acid at about -10° C. to 0° C. for about 3 days toproduce bromo derivatives A3 or A7.

Step Aj: (W=Br; Z and Z'=H; X'=H, Br, Cl or F).

The reaction involves the treatment of bromo derivatives A3, A5 or A7with an alkyl lithium reagent at about -10° C. to 0° C. in diethyl etheror tetrahydrofuran for about 10 to 15 minutes which are then reactedwith two equivalents of the appropriate ester at about -78° C. to about-60° C. for one hour (X'CF₂ CO₂ R, with R being preferably ethyl ormethyl) or with an acid lithium salt (X'CF₂ CO₂ Li) at about -10° C. to0° C. for about one hour followed by hydrolysis with aqueous ammoniumchloride to produce A12.

Step Aj': (W=H, Z and/or Z'=F, X'=H, Br, Cl or F).

The reaction involves the treatment of fluoro derivatives A3, A5 or A7with an alkyl lithium reagent at about -60° C. to -50° C. for about 5-7hours in tetrahydrofuran and those intermediates are reacted with theappropriate ester (X'CF₂ CO₂ R) or acid lithium salt (X'CF₂ CO₂ Li) asdescribed in Step Aj to produce A12.

Step Ak:

Ketone derivatives A12 are treated with sodium borohydride or sodiumcyanoborohydride in ethanol at about 0° C. to 5° C. for one hour toproduce alcohol derivatives A13.

Step Al:

Alcohol derivatives A13 are treated with an acyl chloride (ClCOR₄) inthe presence of triethylamine in dichloromethane at about 0° C. to 5° C.for about 1-3 hours to produce ester derivatives A14.

Step Al':

Following procedure described in Step Al, ester derivatives are treatedwith 1N hydrochloric acid at room temperature for about 15 hours toremove N-protecting group. Free amine derivatives B10 are purified astheir free bases.

Steps Am or Am':

The lithium salt intermediates prepared as described in Steps Aj or Aj'are reacted with carbon dioxide at about -60° C. to -50° C., followed byhydrolysis with aqueous ammonium chloride to produce acid derivativesA15.

Step An:

Acid derivatives A15 are reacted with isobutylchloroformate in thepresence of triethyl amine or N-methyl morpholine in dichloromethane atabout -30° C. to -20° C. for about 30-60 minutes to form mixedanhydrides. Then 1.5-3 equivalents of N,O-dimethylhydroxylaminehydrochloride is added and the reaction is allowed to proceed for fromabout 1-2 hours at about -30° C. to -20° C. and then on additional 1 to2 hours at room temperature to produce dimethyl hydroxamic acidderivatives A16.

Step Ao:

Dimethyl hydroxamic acid derivatives A16 are converted to thepentafluoroketone derivatives A17 by treatment with a pentafluoroethylanion generated in situ by contacting pentafluoro ethyl iodide with amethyl lithium-lithium bromide complex in diethyl ether at about -78° C.for about 5-10 minutes. Then the reaction mixture is allowed to warm to0° C. and hydrolized with aqueous ammonium chloride.

Step Ap:

Methyl ether derivatives A12, A13, A14, A17, A18 or A19 are reacted withboron tribromide in the presence of sodium iodide and 15-crown-5 etherin dichloromethane at about -40° C. to -20° C. for about 3-6 hoursfollowed by hydrolysis at 0° C. with aqueous sodium bicarbonate toproduce benzyl alcohol derivatives A20.

Step Ba:

Carboxylic acid derivatives B1 are reacted with excess of thionylchloride at reflux for about 1-3 hours to produce acylchloridederivatives which are reacted with sodium azide at 0° C. to 10° C. for1-3 hours in acetone-water to produce acyl azide derivatives which areheated in benzene or toluene at about 60° C. to 100° C. for 15-60minutes and then treated with hydrochloric acid at reflux for about30-60 minutes to produce amine hydrochloride salt derivatives B2.

Step Bb:

Amine hydrochloride salt derivatives B2 are converted to their freeamine derivatives with aqueous sodium hydroxide and then the aminemoiety is bis protected with an appropriate group such as trimethylsilylby treating the free amines with two equivalents of an alkyl lithiumreagent at about -60° C. to -40° C. followed by two equivalents ofchlorotrimethylsilane. Then the reaction mixture is stirred one hour atabout -60° C. to -40° C. and allowed to warm to room temperature indiethyl ether or tetrahydrofuran.

Step Bc:

Bis-trimethylsilylated amine derivatives B4 are heated under reflux for1-2 hours in aqueous methanol or ethanol to produce amine derivativesB5.

Step Bd:

Para-Fluorotoluene B15 is treated with an alkyl lithium reagent at about-60° C. to -50° C. for about 5-7 hours in tetrahydrofuran and this litioderivative is treated with an aldehyde or a ketone (R₁ COR₂ or R₂ COCH₂R₃) at about -78° C. to -60° C.

Step Be:

Para-Fluorotoluene derivatives B16 are heated at about 90° C. to 110° C.for about 2-3 hours with cobalt diacetate-tetrahydrate and ethyl methylketone in acetic acid under pressure of oxygen-butane to produce benzoicacid derivatives B1.

Step Ca:

Amine derivatives C1 are protected with an appropriate group such astert-butyloxycarbonyl by reacting the amines withdi-tert-butyldicarbonate in the presence of triethylamine indichloromethane at room temperature for 18 hours to produce N-bocderivatives C2.

Step Cb:

N-boc derivatives C2 are reacted with sodium hydride in tetrahydrofuranfor 3-6 hours at room temperature. The sodium salt intermediates arereacted with an alkyl halide reagent R₉ X (X being preferably Br or I)for 18 hours at room temperature followed by hydrolysis with 1Nhydrochloric acid. Amine derivatives C3 are purified as their free basesafter neutralization of the aqueous medium.

Step Cc:

Amine derivatives C3 are treated with an alkyl lithium reagent intetrahydrofuran at about -60° C. to about -40° C. followed bychlorotrimethylsilane as described in Step Bd or withchlorotrimethylsilane in dichloromethane in the presence oftriethylamine at room temperature for 2-3 hours to produceN-trimethylsilyl derivatives C4, as described in Step Bb.

Step Da:

This reaction involves conversion of the amine derivatives D1 to the"Y^(D) " derivatives D2 as follows:

When Y^(D) =Cl, CN, N₃ :

The amine derivatives D1 are converted to their hydrochloride salts withaqueous hydrochloric acid and treated with sodium nitrite at about 0° C.to 5°0 C. to produce diazonium salts which are heated with cuprouschloride from 20° C. to 60° C. to produce chloro derivatives or treatedwith cuprous cyanide at about 0° C. to 30° C. to produce nitrilederivatives or treated with sodium azide at about 0° C. to 10° C. toproduce azide derivatives.

When Y^(D) =F or NO₂ :

The amine derivatives D1 are dissolved with aqueous hydrochloric acidand treated with sodium nitrite at about 0° C. to 5° C. followed byaqueous fluoroboric acid at about 0° C. to 5° C. The fluoroboratediazonium salt is filtered, dried and is heated gently untildecomposition begins and proceeds smoothly to produce fluoroderivatives. To produce nitro derivatives, fluoroborate diazonium saltsare added to a mixture of aqueous sodium nitrite and copper powder atabout 0° C. to 5° C.

When Y^(D) =Br:

The amine derivatives D1 are dissolved in aqueous hydrobromic acid,treated with sodium nitrite at about 0° C. to 10° C. and then withcopper powder at about 20° C. to 100° C. to produce bromide derivatives.

When Y^(D) =OH:

The amine derivatives D1 are dissolved in aqueous sulfuric acid, treatedwith sodium nitrite at about 0° C. to 5° C. to produce diazonium salt.The diazonium salt solution is slowly added to a boiling aqueoussulfuric acid solution to produce phenol derivatives.

When Y^(D) =SO₃ H:

The amine derivatives D1 are dissolved in concentrated hydrochloric acidand treated with sodium nitrite at about 0° C. to 5° C. Then thediazonium salt is added to a mixture of sulfur dioxide, copper chlorideand potassium chloride in dioxane-benzene. The resulting mixture isheated at about 40° C. to 60° C. for about 1 to 3 hours to producesulfonyl chloride derivatives which are heated under reflux in aqueoussodium carbonate for 1-3 hours to produce sulfonic acid derivatives.

Step Db:

Ester derivatives D2 or D6 are hydrolized with lithium hydroxide inaqueous dimethoxyethane at room temperature for about 1 to 6 hours toproduce alcohol derivatives D3 or D7.

Step Dc:

Alcohol derivatives D3 are oxidized with pyridinium dichromate, or withDess-Martin periodinane oxidant in dichloromethane at about 0° C. to 25°C. for 18 hours or by Swern reaction to produce ketone derivatives D4.

Step Ea (Y^(E) =OR₅):

Phenol derivatives E1 or E5 are converted to their sodium or potassiumsalts with sodium or potassium carbonate in water or acetone at aboutroom temperature and reacted with an alkyl halide reagent R₅ X (X beingpreferably Br or I) at room temperature for 18 hours to produce etherderivatives E2 or E6.

Step Eb:

Benzyl alcohol derivatives E6 dissolved in dichloromethane or chloroformare treated with isobutylene in phosphoric acid-boron trifluorideetherate for about 1 to 3 hours at about -78° C. to -60° C. then 18hours at room temperature or with tert-butyl-2,2,2-trichloroacetamidatein the presence of a catalytic amount of boron trifluoride etherate incyclohexane or in a mixture of cyclohexane-dichloromethane at roomtemperature for about 18-24 hours to produce tert-butyl etherderivatives E7.

Step Ec:

tert-Butyl ether derivatives E8 or E9 are treated with trifluoroaceticacid at about 0° C. to 20° C. for about 18 hours to produce benzylalcohol derivatives E10 or E11.

Step Fa (when Y^(F) =CO₂ R₇):

Nitrile derivatives F1 are heated under reflux for 1-3 hours in aqueoushydrochloric acid to produce acid derivatives (R₄ =H) or heated underreflux for about 3-6 hours with 95% alcohol R₄ OH (R₄ ≠H) saturated withdry hydrochloric acid or with concentrated sulfuric acid to produceester derivatives.

Step Fa (when Y^(F) =COR₆ :

Nitrile derivatives F1 are treated with anhydrous stannous. chloride andhydrogen chloride in diethyl ether or tetrahydrofuran at about 0° C. to20° C. for about 18 hours followed by hydrolysis with cold water toproduce aldehyde derivatives (R₆ =H) or nitrile derivatives are treatedwith a Grignard reagent R₆ MgX (X being preferably Br or I) in diethylether or tetrahydrofuran at about 20° C. to 60° C. for 1-3 hoursfollowed by hydrolysis with aqueous hydrochloric acid to produce ketonederivatives.

Step Ga:

Dibromo derivatives G5 are treated with an alkyl lithium reagent atabout -30° C. to 0° C. in diethyl ether or tetrahydrofuran for about10-20 minutes and those lithium derivative intermediates withparaformaldehyde or with an aldehyde or with a ketone (R₆ COR₇) at about-78° C. to about -60° C. for about one hour to produce benzyl alcoholderivatives G6.

Step Ga':

Fluoro derivatives G7 are treated with an alkyl lithium reagent at about-60° C. to -40° C. in diethyl ether or tetrahydrofuran for 5-7 hours andthose lithium derivative intermediates are reacted with paraformaldehydeor with an aldehyde or with a ketone (R₆ COR7) at about -78° C. to -60°C. for about one hour to produce benzyl alcohol derivatives G10.

Step Sa=steps Aj+Ak+Al; Step Sb=Steps Am+An+Ao+Ak+Al; Step Sc=stepsAj'+Ak+Al; and Step Sd=steps Am'+An+Ao+Al.

For the cyclic derivatives, when R₂ and V--R₃, together with the carbonatom to which R₂ and V are attached, form a 3-6 membered ring:

When V=CH₂ and R₁ =H, CH₃.

Bromobenzene derivatives A1 are reacted with the appropriate cyclicketone (CH₂)₂₋₅ C(O) as described in Step Aa and then by using Step Abor Steps Ad and Ae cycloalkyl derivatives are produced.

When V=O and R₁ =CH₃.

Bromobenzene derivatives A1 are reacted with an halogeno alkyl methylketone X-(CH₂)₁₋₄ C(O)CH₃ (X being Br or Cl) as described in Step Aa andthen the intermediates are heated under reflux for 18 hours to producecycloalkylether derivatives.

When V=O and R₁ =H.

Bromobenzene derivatives A1 are reacted with a halogenoalkylaldehydeX-(CH₂)₁₋₄ CHO) (X being Br or Cl) as described above. Thosehalogenoalkyladehydes are prepared by oxidation of the correspondingalcohols with a mixture of dimethylsulfoxide, pyridine, trifluoraceticacid and dicyclohexyl carbodiimide in benzene or toluene at roomtemperature for 18 hours.

Having generically described the methods for the preparation of thecompounds of this invention, the following specific examples illustratethe chemistry and techniques by which the synthesis may be effected.

EXAMPLE 1 2,2,2-Trifluoro-1-(3-tert-butylphenyl ethanone ##STR13## STEPA: N-Acetyl-4-tert-butyl aniline

A mixture of 20 g (134 mmol) of 4-tert-butyl aniline and 0.044 g (0.67mmol) of zinc powder in 20 ml acetic acid is heated under reflux for 7hours. Then the crude product is poured into 350 ml of ice water andfiltered. Recrystallization in ethanol-water affords 20.83 g (81%) ofthe title compound.

STEP B:

N-Acetyl-2-bromo-4-tert-butyl aniline

To a solution of 20.80 g (108.7 mmol) of N-acetyl-4-tert-butyl anilineand 0.33 g (2 mmol) of ferric chloride in 70 ml of acetic acid is addeddropwise 17.9 g (112 mmol) of bromine while the temperature is keptbetween 30° C. and 40° C. Then the reaction mixture is stirred 4 hoursand poured into 500 ml of ice water. The precipitate is filtered off,washed with water and recrystallized from 70% ethanol. Thus is obtained24.33 g (83%) of title compound.

STEP C:

2-Bromo-4-tert-butyl aniline hydrochloride

A solution of 24.33 g (90 mmol) of N-acetyl-2-bromo-4-tert-butyl anilinein 73.5 ml of 95% ethanol and 46 ml of concentrated hydrochloric acid isheated under reflux one hour. Then the mixture is cooled and the productis filtered, washed with cold 95% ethanol and dried. The yield of titlecompound is 21.75 g (91%).

STEP D: 3-Bromo-tert-butyl benzene

To a solution of 9.34 g (35.3 mmol) of 2-bromo-4-tert-butylhydrochloride in 51 ml of acetic acid, 34 ml of water and 12 ml ofconcentrated hydrochloric acid at 0° C. is added dropwise 2.63 g (38.1mmol) of sodium nitrite in 15 ml of water while temperature is keptbetween 0° C. and 5° C. Then the solution is poured into 40 ml of 50%hypophosphorus acid and 20 ml of water at 0° C. and the total solutionis stirred 3 days at 0° C. The colored oil formed is removed by use ofseparatory funnel, dissolved in ethyl acetate, washed with water andbrine and dried over magnesium sulfate. Ethyl acetate is removed andtitle compound is purified by distillation. The yield of3-bromo-tert-butyl benzene is 6.01 g (80%); b.p.: 108° C./16 mmHg.

STEP E:

2,2,2-Trifluoro-1-(3-tert-butyl)phenyl ethanone

To a solution of 5.85 g (27.5 mmol) of 3-bromo-tert-butyl benzene in 55ml of diethyl ether at 0° C. is added dropwise 18.5 ml of 1.5Mn-butyllithium in hexane. The reaction mixture is stirred 10 minutes at0° C. and cooled to -78° C. Then 11.71 g (82.5 mmol) of ethyltrifluoroacetate is added dropwise and the reaction mixture is stirredone hour at -78° C. Cooling bath is removed and when the temperaturerised to 0° C., 100 ml of 3N hydrochloric acid is added. The organiclayer is separated, washed with water and brine, dried over magnesiumsulfate and concentrated. Chromatography on silica gel (2% of ethylacetate in petroleum ether) followed by distillation afforded 0.73 g oftitle compound (11.5% ); b.p.: 142° C./22 mmHg.

EXAMPLE 2 2,2,2-Trifluoro-1-(3-tert-butyl)phenyl ethanol ##STR14##

To a solution of 0.46 g (2 mmol) of2,2,2-trifluoro-1-(3-tert-butyl)phenyl ethanone in 10 ml of ethanol at0° C. is added 0.08 g (2.1 mmol) of sodium borohydride. The reactionmixture is stirred one hour at room temperature, cooled to 0° C. andhydrolized with 1.28 g (24 mmol) of ammonium chloride in 20 ml of water.Ethanol is removed under reduced pressure and crude product is extractedwith ethyl acetate. The organic layer is washed with brine, dried overmagnesium sulfate and concentrated. Title compound is purified bychromatography on silica gel (5% of ethyl acetate in petroleum ether).

EXAMPLE 3 [2,2,2-Trifluoro-1-(3-tert-butyl)phenyl]ethyl acetate##STR15##

To a solution of 0.30 g (1.3 mmol) of2,2,2-trifluoro-1-(3-tert-butyl)phenyl ethanol and 0.13 g (1.3 mmol) oftriethylamine in 5 ml of dichloromethane at 0° C. is added dropwise 0.10g (1.3 mmol) of acetyl chloride in 2 ml of dichloromethane. The reactionmixture is stirred 3 hours at room temperature, washed with water,brine, dried over magnesium sulfate and concentrated. Title compound ispurified by chromatography on silica gel (2% of ethyl acetate inpetroleum ether).

EXAMPLE 4 2,2,2-Trifluoro-1-[3-(2-propyl methyl ether)]phenyl ethanone##STR16## STEP A: 1-Bromo-3-(2-propanol)benzene

To a solution of 5.90 g (25 mmol) of 1,3-dibromobenzene in 25 ml oftetrahydrofuran at -30° C. is added dropwise 17 ml (25.5 mmol) of 1.5Mn-butyllithium in hexane. Then the reaction mixture is stirred 10minutes at -30° C. and cooled to -78° C. To the solution is addeddropwise 1.74 g (30 mmol) of acetone in 10 ml of tetrahydrofuran and thereaction mixture is stirred 30 minutes at -78° C. Cooling bath isremoved and when the temperature rises to 0° C., 50 ml of 1Nhydrochloric acid is added dropwise, followed by 50 ml of ethyl acetate.The organic layer is removed, washed with water, brine, dried overmagnesium sulfate and concentrated. Chromatography on silica gel (5% ofethyl acetate in petroleum ether) affords 2.72 g (51%) of titlecompound.

STEP B:

1-Bromo-3-(2-propylmethylether)benzene

A solution of 2.72 g (12.65 mmol) of 1-bromo-3-(2-propanol)benzene in 15ml of tetrahydrofuran is added dropwise in 0.51 g (12.70 mmol) of 60%sodium hydride in 15 ml of tetrahydrofuran at 0° C. Then the reactionmixture is stirred 3 hours at room temperature and 2.15 g (15.15 mmol)of methyl iodide in 7 ml of tetrahydrofuran is added dropwise. Theresulting mixture is stirred at room temperature for 18 hours, treatedwith 30 ml of 1N hydrochloride and extracted with 30 ml of ethylacetate. The organic layer is separated, washed with water, brine, driedover magnesium sulfate and concentrated. Chromatography on silica gel(2% of ethyl acetate in petroleum ether) affords 1.62 g (56%) of titlecompound.

STEP C:

2,2,2-Trifluoro-1-[3-(2-propyl methyl ether)]phenyl ethanone

To a solution of 0.81 g (3.5 mmol) of1-bromo-3-(2-propylmethylether)benzene in 5 ml of tetrahydrofuran at-40° C. is added dropwise 2.4 ml (3.6 mmol) of 1.5M n-butyl-lithium inhexane. Then the reaction mixture is stirred 30 minutes at -40° C.,cooled to -78° C. and 0.99 g (7 mmol) of ethyl acetate is addeddropwise. The resulting reaction mixture is stirred 30 minutes at -78°C. and cooling bath is removed. At 0° C. 10.5 ml of 1N hydrochloric acidis added followed by 10 ml of ethyl acetate. The organic layer isremoved, washed with water and brine, dried over magnesium sulfate andconcentrated. Chromatography on silica gel (10% of ethyl acetate inpetroleum ether) affords 0.39 g (45%) of the title compound.

EXAMPLE 5 2,2,2-Trifluoro-1-[3-(2-propanol)]phenyl ethanone ##STR17##

To a mixture of 0.30 g (1.2 mmol) of2,2,2-trifluoro-1-[3-(2-propylmethylether)]phenyl ethanone and 0.72 g(4.8 mmol) of sodium iodide in 5 ml of dichloromethane at -40° C. isadded dropwise 1.06 g (4.8 mmol) of 15-crown-5 in 10 ml ofdichloromethane. The reaction mixture is stirred 10 minutes at -40° C.and 3.6 ml of a 1.0M solution of borontribromide in dichloromethane isadded dropwise. Then the resulting reaction mixture is stirred 3 hoursat -40° C., allowed to warm to 0° C., and hydrolized with 10 ml ofsaturated aqueous sodium bicarbonate. The organic layer is separated,washed with water and brine, dried over magnesium sulfate andconcentrated. Chromatography on silica gel (20% of ethyl acetate inpetroleum ether) affords title compound.

EXAMPLE 6 2,2,2-Trifluoro-1-[2-fluoro-5-(1-diethylether)]phenyl ethanone##STR18## STEP A: 4-(1-Diethylether)-1-fluorobenzene

A solution of 1.40 g (10 mmol) of 1-(4-fluorophenyl)ethanol in 10 ml oftetrahydrofuran is added dropwise on 0.40 g (10 mmol) of 60% sodiumhydride in 10 ml of tetrahydrofuran at 0° C. Then the reaction mixtureis stirred 3 hours at room temperature and 1.56 g (10 mmol) of ethyliodide in 10 ml of tetrahydrofuran is added dropwise. The resultingmixture is stirred at room temperature for 18 hours, treated with 20 mlof 1N hydrochloric acid and extracted with 30 ml of ethyl acetate. Theorganic layer is separated, washed with water, brine, dried overmagnesium sulfate and concentrated. Chromatography on silica gel (2% ofethyl acetate in petroleum ether) affords title compound.

STEP B:

2,2,2-Trifluoro-1-[3-(2-diethylether)-6-fluoro]phenyl ethanone

To a solution of 0.84 g (5 mmol) of 4-(1-diethylether)-1-fluorobenzenein 10 ml of tetrahydrofuran at -50° C. is added dropwise 3.33 ml (5mmol) of 1.5M n-butyllithium in hexane. The reaction mixture is stirred6 hours at -50° C. and cooled to -78° C. Then 1.42 g (10 mmol) of ethyltrifluoro acetate in 5 ml of tetrahydrofuran is added dropwise and themixture is stirred 30 minutes at -78° C. Cooling bath is removed and at0° C. 15 ml of 1N hydrochloric acid is added dropwise followed by 20 mlof ethyl acetate. The organic layer is removed, washed with water andbrine, dried over magnesium sulfate and concentrated. Chromatography onsilica gel (10% of ethyl acetate in petroleum ether) affords titlecompound.

EXAMPLE 7 2,2,2-Trifluoro-1-(2-fluoro-3-isopropyl)phenyl ethanone##STR19## STEP A: 2-(2-Fluoro)phenyl-2-propanol

To a solution of 20 ml (30 mmol) of 1.5M n-butyllithium in hexanediluted with 10 ml of tetrahydrofuran at -78° C. is added dropwise asolution of 5.25 g (30 mmol) of 2-bromo-1-fluorobenzene in 30 ml oftetrahydrofuran. 5 minutes later a solution of 2.03 g (35 mmol) ofacetone in 10 ml of tetrahydrofuran is added dropwise. Cooling bath isremoved and at 0° C. 30 ml of 3N hydrochloric acid is added dropwise.The reaction mixture is extracted with 60 ml of ethyl acetate and theorganic layer is washed with water and brine, dried over magnesiumsulfate and concentrated. Title compound is purified by distillation.

STEP B:

2-(2-Fluoro)phenyl-2-propyl p-toluenesulfonate

To a solution of 2.08 g (20 mmol) of 2-(2-fluoro)phenyl-2-propanol in 10ml of pyridine, cooled to 0° C., is added dropwise 4.20 g (22 mmol) ofp-toluenesulfonylchloride in 5 ml of pyridine, and the resulting mixtureis stirred at 0° C. for 18 hours. The reaction mixture is poured into100 ml of water and extracted with 50 ml of ethyl acetate. The organiclayer is separated, washed with water and brine, dried over magnesiumsulfate and concentrated. Recrystallization from hexane affords titlecompound.

STEP C:

2-Isopropyl-1-fluorobenzene

To a solution of 4.62 g (15 mmol) of 2-(2-fluoro)phenyl-2-propylp-toluenesulfonate in 150 ml of di-n-butyl ether is added dropwise 18 ml(18 mmol) of 1M lithium aluminum hydride in tetrahydrofuran. Then thereaction mixture is stirred at 100° C. for 4 hours, cooled to 0° C. and2 ml of water is added dropwise. The resulting mixture is filtered,washed with water and brine, dried over magnesium sulfate andconcentrated. Title compound is purified by distillation.

STEP D:

2,2,2-Trifluoro-1-(2-fluoro-3-isopropyl)phenyl ethanone

Title compound is prepared as described in Step B of Example 6 andpurified by chromatography on silica gel (10% ethyl acetate in petroleumether) followed by distillation.

EXAMPLE 82,2,2-Trifluoro-1-[2-fluoro-3-(N,N-dimethylamino)-5-(1-diethylether)]phenylethanone ##STR20## STEP A: 2-Fluoro-5-(1-diethylether) benzoic acid

To a solution of 6.72 g (40 mmol) of 4-(1-diethylether)-1-fluorobenzenein 60 ml of tetrahydrofuran at -50° C. is added dropwise 26.7 ml (40mmol) of 1.5M n-butyllithium in hexane. The reaction mixture is stirred6 hours at -50° C. and treated with excess of carbon dioxide. Thencooling bath is removed and, at 0° C., 60 ml of water is added dropwise.Tetrahydrofuran is removed under reduced pressure and the aqueoussolution is extracted twice with 30 ml of n-hexane. The aqueous layer isacidified with 20 ml of 4N hydrochloric acid, extracted twice with 50 mlof ethyl acetate. The organic layers are combined, washed with brine,dried over magnesium sulfate and concentrated. Title compound isrecrystallized from isopropanol.

STEP B:

N-(tert-Butoxycarbonyl)-[2-fluoro-5-(1-diethylether]aniline

A mixture of 6.36 g (30 mmol) of 2-fluoro-5-(1-diethylether)benzoic acidand 5.35 g (45 mmol) of thionyl chloride is heated 2 hours at 60° C.Then gases and excess of thionyl chloride are removed under reducedpressure. The crude product is dissolved in 20 ml of acetone and 2.60 g(40 mmol) of sodium azide in 20 ml of water is added dropwise. Thereaction mixture is stirred 1 hour at 0° C. and acetone is removed underreduced pressure. To the aqueous mixture is added 40 ml of ethylacetate, then the organic layer is separated, washed with brine anddried over magnesium sulfate. Ethyl acetate is removed under reducedpressure and the crude product is dissolved in 40 ml of benzene andheated under reflux for 1 hour. Then the reaction mixture is cooled to0° C. and 20 ml of concentrated hydrochloric acid is added. Theresulting mixture is heated under reflux for 30 minutes and cooled.Benzene is removed and 100 ml of 3N sodium hydroxide solution is addedto the aqueous mixture, followed by 100 ml of ethyl acetate. The organiclayer is separated, washed with brine, dried over magnesium sulfate andconcentrated. The crude material is dissolved in 80 ml ofdichloromethane and 4.04 g (40 mmol) of triethylamine was added. To theresulting mixture is added dropwise 9.60 g (44 mmol) of di-tert-butyldicarbonate in 20 ml of dichloromethane and the reaction mixture isstirred at room temperature for 18 hours. Then dichloromethane andtriethylamine are removed under reduced pressure and title compound ispurified by chromatography on silica gel (10% of ethyl acetate inpetroleum ether).

STEP C:

N-Methyl-[2-fluoro-5-(1-diethylether)]aniline

A solution of 4.23 g (15 mmol) ofN-(tert-butoxycarbonyl)-[2-fluoro-5-(1-diethylether)]aniline in 15 ml oftetrahydrofuran is added dropwise to 0.60 g (15 mmol) of 60% sodiumhydride in 15 ml of tetrahydrofuran at 0° C. Then the reaction mixtureis stirred 3 hours at room temperature and 2.55 g (19 mmol) of methyliodide in 15 ml of tetrahydrofuran is added dropwise. The resultingmixture is stirred at room temperature for 18 hours, cooled to 0° C. and15 ml of concentrated hydrochloric acid is added dropwise. Stirring iscontinued for 3 hours at room temperature and tetrahydrofuran is removedunder reduced pressure. To the aqueous medium, 70 ml of 3N sodiumhydroxide solution is added dropwise, followed by 60 ml of ethylacetate. The organic layer is separated, washed with brine, dried overmagnesium sulfate and concentrated. The crude product is dissolved in 15ml of diethyl ether and treated with 15 ml of a saturated solution ofhydrochloric acid in diethyl ether. The hydrochloride salt is filteredand recrystallized from isopropanol-diethyl ether. The resulting salt isdissolved in 10 ml of water and to the aqueous medium is added 10 ml ofa saturated sodium carbonate solution followed by 20 ml of ethylacetate. The organic layer is separated, washed with brine, dried overmagnesium sulfate and concentrated to afford the title compound.

STEP D:

N,N-Dimethyl-[2-fluoro-5-(1-diethylether]aniline

Title compound (adding another methyl group) is prepared as described inStep C.

STEP E:

2,2,2-Trifluoro-1-[2-fluoro-3-(N,N-dimethylamino)-5-(1-diethylether)]phenylethanone

Title compound is prepared as described in Step B of Example 6 exceptfor work-up procedure. After hydrolysis with 3N hydrochloric acid,tetrahydrofuran is removed under reduced pressure and the aqueoussolution is extracted twice with ethyl acetate, the aqueous medium isbasified with a saturated sodium carbonate solution and extracted twicewith ethyl acetate. The organic layers are combined, washed with brine,dried over magnesium sulfate and concentrated. The crude product isdissolved in diethyl ether and treated with a saturated solution ofhydrochloric acid in diethyl ether. The hydrochloride salt is filteredand recrystallized from isopropanol-diethyl ether. The resulting salt isdissolved in water and treated with a saturated sodium carbonatesolution. The resulting aqueous medium is extracted with ethyl acetate.The ethyl acetate solution is washed with brine, dried over magnesiumsulfate and concentrated to afford title compound.

It is now established that Alzheimer's disease and other seniledegenerative diseases such as senile dementia are characterized by aselective loss in the cerebral cortex of choline acetyltransferase, theenzyme responsible for the biosynthesis of acetylcholine. There alsoexists a good correlation between memory impairment or dementia and thedecrement in cholinergic transmission. Thus, impaired cholinergictransmission in the central nervous system may be, at least in part,responsible for the symptomatology of Alzheimer's disease and seniledementia. In support to these conclusions such compounds asphysostigmine and 1,2,3,4-tetrahydro-9-aminoacridine (THA), compoundswhich prevent the catabolism of acetylcholine have found a place in thetreatment of Alzheimer's and other senile degenerative diseases. Indeed,it has been recognized that the extent of improvement of cognitivefunctions has been closely related to the degree of inhibition ofacetylcholinesterase.

The compounds of the present invention are useful in treating otherconditions responsive to inhibition of acetylcholinesterase such asMyasthenia Gravis [J. Neurol Neurosurg. Psychiatry, 46 (10) 1983,929-935, Neurology 42 (6) 1992, 1153-1156], antidotes against poisoningwith organophosphates [see U.S. Pat. No. 5,171,750, Int. J. Clin.Pharmacol. Ther. Toxicol. 27 (8) 1989, 367-387], and glaucoma (Arch.Clin. Exp. Ophthalmol. 229 (3), 1991, 252-253)

The compounds of Formula I are pharmacologically active agents capableof inhibiting acetylcholinesterase as demonstrable in standardbiological in vitro and in vivo test procedures. Indeed, based uponstandard laboratory procedures, it is to be shown that the compounds ofFormula I are potent and selective, quasi irreversible inhibitors ofacetylcholinesterase capable of demonstrating advantages over the priorart, particularly physostigmine, in their use in the treatment ofAlzheimer's disease and senile dementia. The compounds, in general, willexert their acetylcholinesterase inhibitory properties within the doserange of about 0.01 mg to 5 mg per kilogram of body weight for thepreferred compounds.

For pharmacological end-use applications, the compounds of Formula I arepreferentially administered in the form of their pharmaceuticallyacceptable acid addition salts. Of course, the effective dosage of thecompounds will vary according to the individual potency of each compoundemployed, the severity and nature of the disease being treated and theparticular subject being treated. In general, effective results can beachieved by administering a compound at a dosage of about 0.01 mg toabout 20 mg per kilogram of body weight per day, administeredsystemically. Therapy should be initiated at lower dosages. The dosagethereafter may be administered orally in solid dosage forms, e.g.,capsules, tablets, or powders, or in liquid forms, e.g., solutions orsuspensions. The compounds may also be injected parenterally in the formof sterile solutions or suspensions.

In practicing the method of this invention, the active ingredient ispreferably incorporated in a composition comprising a pharmaceuticalcarrier and from about 5 to about 90 percent by weight of a compound ofthe invention or a pharmaceutically-acceptable salt thereof. The term"pharmaceutical carrier" refers to known pharmaceutical excipientsuseful in formulating pharmaceutically active compounds for internaladministration to animals, and which are substantially non-toxic andnon-sensitizing under conditions of use. The compositions can beprepared by known techniques for the preparation of tablets, capsules,elixirs, syrups, emulsions, dispersions and wettable and effervescentpowders, and can contain suitable excipients known to be useful in thepreparation of the particular type of composition desired.

The preferred route of administration is oral administration. For oraladministration the formula I compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions. The solid unitdosage forms can be a capsule which can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers such as lactose, sucrose, calciumphosphate, and cornstarch. In another embodiment the compounds of thisinvention can be tableted with conventional tablet bases such aslactose, sucrose, and cornstarch in combination with binders such asacacia, cornstarch, or gelatin, disintegrating agents intended to assistthe break-up and dissolution of the tablet following administration suchas potato starch, alginic acid, corn starch, and guar gum, lubricantsintended to improve the flow of tablet granulations and to prevent theadhesion of tablet material to the surfaces of the tablet dies andpunches, for example, talc, stearic acid, or magnesium, calcium, or zincstearate, dyes, coloring agents, and flavoring agents intended toenhance the aesthetic qualities of the tablets and make them moreacceptable to the patient. Suitable excipients for use in oral liquiddosage forms include diluents such as water and alcohols, for example,ethanol, benzyl alcohol, and the polyethylene alcohols, either with orwithout the addition of a pharmaceutically acceptable surfactant,suspending agent, or emulsifying agent.

The formula I compounds of this invention may also be administeredparenterally, that is, subcutaneously, intravenously, intramuscularly,or interperitoneally, as injectable dosages of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid or mixture of liquids such as water, saline,aqueous dextrose and related sugar solutions, an alcohol such asethanol, isopropanol, or hexadecyl alcohol, glycols such as propyleneglycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as polyethyleneglycol 400, an oil, a fatty acid, a fatty acid ester or glyceride, or anacetylated fatty acid glyceride with or without the addition of apharmaceutically acceptable surfactant such as a soap or a detergent,suspending agent such as pectin, carbomers, methylcellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutically acceptable adjuvants. Illustrative ofoils which can be used in the parenteral formulations of this inventionare those of petroleum, animal, vegetable, or synthetic origin, forexample, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil,olive oil, petrolatum, and mineral oil. Suitable fatty acids includeoleic acid, stearic acid, and isostearic acid. Suitable fatty acidesters are, for example, ethyl oleate and isopropyl myristate. Suitablesoaps include fatty alkali metal, ammonium, and triethanolamine saltsand suitable detergents include cationic detergents, for example,dimethyl dialkyl ammonium halides, alkyl pyridinium halides; anionicdetergents, for example, alkyl, aryl, and olefin sulfonates, alkyl,olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and polyoxyethylenepolypropylene copolymers; and amphoteric detergents,for example, alkyl beta-aminopropionates, and 2-alkylimidazolinequarternary ammonium salts, as well as mixtures. The parenteralcompositions of this invention will typically contain from about 0.5 toabout 25% by weight of the formula I compound in solution. Preservativesand buffers may also be used advantageously. In order to minimize oreliminate irritation at the site of injection, such compositions maycontain a non-ionic surfactant having a hydrophile-lipophile balance(HLB) of from about 12 to about 17. The quantity of surfactant in suchformulations ranges from about 5 to about 15% by weight. The surfactantcan be a single component having the above HLB or can be a mixture oftwo or more components having the desired HLB. Illustrative ofsurfactants used in parenteral formulations are the class ofpolyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients. Preferably topical administration will be accomplishedusing a patch either of the reservoir and porous membrane type or of asolid matrix variety.

Some suitable transdermal devices are described in U.S. Pat. Nos.3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generallycontain a backing member which defines one of its face surfaces, anactive agent permeable adhesive layer defining the .other face surfaceand at least one reservoir containing the active agent interposedbetween the face surfaces. Alternatively, the active agent may becontained in a plurality of microcapsules distributed throughout thepermeable adhesive layer. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

In another device for transdermally administering the compounds inaccordance with the present invention, the pharmaceutically activecompound is contained in a matrix from which it is delivered in thedesired gradual, constant and controlled rate. The matrix is permeableto the release of the compound through diffusion or microporous flow.The release is rate controlling. Such a system, which requires nomembrane is described in U.S. Pat. No. 3,921,636. At least two types ofrelease are possible in these systems. Release by diffusion occurs whenthe matrix is non-porous. The pharmaceutically effective compounddissolves in and diffuses through the matrix itself. Release bymicroporous flow occurs when the pharmaceutically effective compound istransported through a liquid phase in the pores of the matrix.

What is claimed is:
 1. A method of treating degenerative dementias by administering to a patient in need of such therapy an effective amount of a compound of Formula I ##STR21## stereoisomers or pharmaceutically acceptable salts thereof, wherein each of Z and Z' are independently H or F;Q is ##STR22## CH(OH), or ##STR23## X is H, Br, Cl, F or CF₃ ; Y is H, Br, Cl, F, OH, OR₅, OC(O)R₄ N₃, CN, NO₂, SO₃ H, CO₂ R₄, NH₂, NR₉ R'₉, C(R₆)(R₇)(V'R₈) or C(O)R₇, provided that when both Z and Z' are F, then Y is H or F; V and V' are each independently CH₂ or O; R₁ is H or CH₃ ; R₂, R₉ and R'₉ are each independently (C₁₋₆)alkyl; R₃, R₆, R₇ and R₈ are each independently H or (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl; or R₂ and V--R₃ taken together with the carbon atom to which they are attached form a 3-6 membered ring; R₄ is H, (C₁₋₁₀)alkyl, (C₀₋₄)alkylene aryl or (C₃₋₈)cycloalkyl; and R₅ is (C₁₋₁₀)alkyl, benzyl, phenethyl or (C₃₋₆)cycloalkyl.
 2. The method of claim 1 wherein Q is C(O).
 3. The method of claim 1 wherein X is F.
 4. The method of claim 1 wherein each of Z, Z' and Y are hydrogen.
 5. The method of claim 1 wherein R₁, R₂, V and R₃ are respectively methyl, methyl, methylene and hydrogen.
 6. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-(3-tert-butyl)phenyl ethanone.
 7. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-(3-tert-butyl)phenyl ethanol.
 8. The method of claim 1 wherein the compound is [2,2,2-Trifluoro-1-(3-tert-butyl)phenyl]ethyl acetate.
 9. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-[3-(2-propyl methyl ether)]phenyl ethanone.
 10. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-[3-(2-propanol)]phenyl ethanone.
 11. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-[2-fluoro-5-(1-diethylether)]phenyl ethanone.
 12. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-(2-fluoro-3-isopropyl)phenyl ethanone.
 13. The method of claim 1 wherein the compound is 2,2,2-Trifluoro-1-[2-fluoro-3-(N,N-dimethylamino)-5-(1-diethylether)]phenyl ethanone. 